(Gem-heterocyclodimethanamine-N,N&#39;)platinum complexes

ABSTRACT

Organic platinum complexes active as anti-tumor agents in warm-blooded animals, and methods for synthesis of same, are described.

SUMMARY OF THE INVENTION

This invention is concerned with new organic compounds of the formulae:##STR1## where n and n' are integers 0-3; A is selected from the groupconsisting of O, ##STR2## N-alkyl(C₁ -C₅) and NCO-alkyl-(C₁ -C₅); L andL' are selected from the group consisting of halide, nitrate, sulfate,and a monobasic carboxylate such as acetate, hydroxy acetate andpropionate; or L and L' taken together may be a dibasic carboxylateselected from the group consisting of: ##STR3## or L and L' takentogether may be a tribasic carboxylate selected from the groupconsisting of ##STR4## or L and L' taken together is ascorbic acid and Xis selected from the group consisting of halogen and hydroxy.

The compounds of this invention may be prepared according to thefollowing reaction schemes: ##STR5##

According to Flowchart A tribromopentaerythritol (1) is reacted withpotassium hydroxide in methanol at reflux temperature, giving3,3-bis(bromomethyl) oxetane (2) which is reacted with ammonia inmethanol in a sealed condition, then with sodium methoxide and finallyhydrochloric acid, giving 3,3-oxetanedimethanamine, dihydrochloride (3).Reaction of (3) with sodium acetate and potassium tetrachloroplatinatein water gives the product (4).

Product (4) may then be reacted with silver nitrate in water, giving thenitrate derivative (5) which is then reacted with a dibasic organic acidHL-L'H in the presence of two equivalents of sodium hydroxide giving theproducts (6). ##STR6##

According to Flowchart B dichloroethyl ether (7) and malononitrile (8)are reacted with potassium carbonate in acetonitrile at reflux, givingtetrahydro-4H-pyran-4,4-dicarbonitrile (9) which is then reacted with 1Nborane in tetrahydrofuran followed by treatment with hydrochloric acid,giving tetrahydro-4H-pyran-4,4-dimethanamine dihydrochloride (10) whichis then reacted with sodium acetate and potassium tetrachloroplatinatein water, giving the product (11). ##STR7## In Flowchart C, compound 13is derived by treating 12 with chlorine gas in dilute hydrochloric acid.##STR8## In Flowchart D, compound 15 is derived by treating 14 withhydrogen peroxide.

The novel complexed compounds of this invention possess the property ofinhibiting the growth of tumors in mammals as established by thefollowing tests.

LYMPHOCYTIC LEUKEMIA P388 TEST

The animals used were BDF/1 mice, all of one sex, weighing a minimum of18 g and all within a 3 g weight range. There were 5 or 6 animals pertest group. The tumor transplant was by intraperitoneal injection of 0.5ml of dilute ascitic fluid containing 10⁶ cells of lymphocytic leukemiaP388. The test compounds were administered intraperitoneally on days 1,5 and 9 relative to tumor inoculation, at various doses. The animalswere weighed and the survivors recorded on a regular basis for 30 days.The median survival time and the ratio of survival time for treated(T)/control (C) animals were calculated. The positive control compoundwas Cisplatin. The results of this test with representative compounds ofthis invention appear in Table I.

                  TABLE I                                                         ______________________________________                                        Lymphocytic Leukemia P388 Test                                                                            Median                                                                        Survi-  T/                                                           Dose     val     C × 100                             Compound           (mg/kg)  (Days)  (%)                                       ______________________________________                                        dichloro(3,3-oxetanedimthan-                                                                     12.5     21      193                                       amine- .sub.--N, .sub.--N')platinum                                                              6.2      18      165                                                          3.1      15      138                                       Control            --       10.9    --                                        Cisplatin          1        20.5    188                                                          0.25     15      138                                                          0.06     11.5    106                                       (3,3-oxetanedimethanamine-                                                                       50       25      253                                        .sub.--N, .sub.--N')[propanedioato(2-)-O.sup.1,O.sup.3 ]-                                       25       21      212                                       platinum           12.5     19      192                                                          6.2      12.5    126                                                          3.1      13.5    136                                                          1.5      11.5    116                                       Control            --       9.9     --                                        Cisplatin          1        20      202                                                          0.25     12.5    126                                                          0.06     11      111                                       bis(acetato-O)(3,3-oxetane-                                                                      12.5     21.5    217                                       dimethanamine- .sub.--N, .sub.--N')platinum                                                      6.2      17      172                                                          3.1      11.5    116                                                          1.5      11      111                                       Control            --       9.9     --                                        Cisplatin          1        20      202                                                          0.25     12.5    126                                                          0.06     11      111                                       [1,1,2-ethanetricarboxylato(2-)-                                                                 50       18.5    162                                       O.sup.1,O.sup.1 ](3,3-oxetanedimethanamine-                                                      25       16      140                                        .sub.--N, .sub.--N']platinum                                                                    12.5     16.5    145                                                          6.2      13      114                                                          3.1      12.5    110                                                          1.5      12      105                                       Control            --       11.4    --                                        Cisplatin           1       16      140                                                          0.25     11       97                                       bis(butanoato-O)(3,3-oxetane-                                                                    25       24      218                                       dimethanamine- .sub.--N, .sub.--N')platinum                                                      12.5     19      173                                                          6.2      18      164                                                          3.1      15      136                                       Control            --       11      --                                        Cisplatin          1        14.5    132                                                          0.25     13.5    123                                       [3,4-dihydroxy-3-cyclobutene-                                                                    25       12.5    114                                       1,2-diaonato(2-)-O.sup.3,O.sup.4 ](3,3-oxe-                                                      12.5     21.5    195                                       tanedimethanamine- .sub.--N, .sub.--N')platinum                                                  6.2      15.5    141                                                          3.1      13      118                                       Control            --       11      --                                        Cisplatin          1        14.5    132                                                          0.25     13.5    123                                       [1,1-cyclobutanedicarboxylato-                                                                   50       24      218                                       (2-)-O.sup.1,O.sup.1 ](3,3-oxetanedi-                                                            25       20      182                                       methanamine- .sub.--N, .sub.--N')platinum                                                        12.5     16.5    150                                                          6.2      11.5    105                                                          3.1      12      109                                       Control            --       11      --                                        Cisplatin          1        14.5    132                                                          0.25     13.5    123                                       (3,3-oxethanedimethanamine- .sub.--N, .sub.--N')-                                                12.5     20.5    186                                       [[2,2'-oxybis[acetato]](2-)-                                                                     6.2      12.5    114                                       O.sup.1,O.sup.1 ]platinum                                                                        3.1      13      118                                       Control            --       11      --                                        Cisplatin          1        14.5    132                                                          0.25     13.5    123                                       (3,3-oxetanedimethanamine-                                                                       100      17      155                                        .sub.--N, .sub.--N',)[propanedioato(2-)-O.sup.1,O.sup.3 ]-                                      50       21.5    195                                       platinum           25       14.5    132                                                          12.5     14      127                                                          6.2      12      109                                                          3.1      12      109                                       Control            --       11      --                                        Cisplatin          1        14.5    132                                                          0.25     13.5    123                                       (3,3-oxetanedimethanamine-                                                                       100      10.5    105                                        .sub.--N, .sub.--N',)[pentanedioato(2-)-O.sup.1,O.sup.5 ]-                                      50       18.5    185                                       platinum           25       16      160                                                          12.5     14      140                                                          6.2      13      130                                                          3.1      12      120                                       Control            --       10      --                                        Cisplatin          1.25     25.5    255                                                          0.62     20.5    205                                       ______________________________________                                    

MELANOTIC MELANOMA B16

The animals used were C57BC/6 mice, all of the same sex, weighing aminimum of 17 g and all within a 3 g weight range. There were 10 animalsper test group. A 1 g portion of melanotic melanoma B₁₆ tumor washomogenized in 10 ml of cold balanced salt solution and a 0.5 ml aliquotof the homogenate was implanted intraperitoneally into each of the testmice. The test compounds were administered intraperitoneally on days 1through 9, relative to tumor inoculation, at various doses. The animalswere weighed and survivors recorded on a regular basis for 60 days. Themedian survival time for treated (T)/control (C) animals werecalculated. The positive control compound was Cisplatin. The results ofthis test appear in Table II.

                  TABLE II                                                        ______________________________________                                        Melanotic Melanoma B16 Test                                                                             Median                                                               Dose     Survival T/C × 100                            Compound         (mg/kg)  (Days)   (%)                                        ______________________________________                                        (3,3-oxetanedimethanamine-                                                                     25       30       176                                         .sub.--N, .sub.--N')[propanedioato(2-)-O.sup.1,O.sup.3 ]-                                     12       30       176                                        platinum         6        27.5     162                                        Control          --       17       --                                         Cisplatin        0.5      22.5     132                                                         0.25     25       147                                        bis(acetato-O)(3,3-oxetane-                                                                    3        23       135                                        dimethanamine- .sub.--N, .sub.--N')platinum                                                    1.5      19       112                                                         0.8      24.5     144                                        Control          --       17       --                                         Cisplatin        0.5      22.5     132                                                         0.25     25       147                                        bis(butanoato-O)(3,3-oxetane-                                                                  3        26       153                                        dimethanamine- .sub.--N, .sub.--N')platinum                                   Control          --       17       --                                         Cisplatin        0.5      22.5     132                                                         0.25     25       147                                        [1,1-cyclobutanedicarboxylato-                                                                 12       20.5     121                                        (2-)-O.sup.1 ,O.sup.1 ](3,3-oxethanedimeth-                                                    6        26       153                                        anamine- .sub.--N, .sub.--N')platinum                                                          3        20       118                                                         1.5      20.5     121                                        Control          --       17       --                                         Cisplatin        0.5      22.5     132                                                         0.25     25       147                                        dichlorc(3,3-oxetanedimethan-                                                                  1.5      26       137                                        amine- .sub.--N, .sub.--N')platinum                                                            0.8      21.5     113                                        Control          --       19       --                                         Cisplatin        0.4      29.5     155                                                         0.2      25.5     134                                                         0.1      20.5     108                                        ______________________________________                                    

COLON 26 ADENOCARCINOMA TEST

The animals used were Balb/C mice all of one sex, weighing a minimum of17 g and all within a 3 g weight range. There were 5 or 6 mice per testgroup with three groups of 5 or 6 animals used as untreated controls foreach test. The tumor implant was by intraperitoneal (or subcutaneous)injection of 0.5 ml of a 2% Colon 26 tumor brei in Eagle's MEM mediumcontaining antibiotics. The test compounds were administeredintraperitoneally on days 1, 5 and 9 (relative to tumor implant doses).The mice were weighed and deaths recorded on a regular basis for 30days. The median survival times and the ratio of survival time fortreated (T)/control (C) animals were calculated. The positive controlcompound was Cisplatin. The results of this test on representativecompounds of this invention appear in Table III.

                  TABLE III                                                       ______________________________________                                        Colon 26 Adenocarcinoma Test                                                                              Median                                                                        Survi-  T/                                                           Dose     val     C × 100                             Compound           (mg/kg)  (Days)  (%)                                       ______________________________________                                        (3,3-oxethanedimethanamine- .sub.--N, .sub.--N')-                                                50       27.5    172                                       [propanedioato(2-)O.sup.1,O.sup.3 ]platinum                                                      25       30      188                                                          12       26      163                                                          6        21      131                                       Control            --       16      --                                        Cisplatin          1        25      156                                                          0.5      18      113                                                          0.25     18      113                                       bis(acetato-O)(3,3-oxetanedim-                                                                   12       19.5    118                                       ethanamine- .sub.--N, .sub.--N')platinum                                                         6        22.5    136                                                          3        19      115                                                          1.5      17.5    106                                       Control            --       16.5    --                                        Cisplatin          1        23      139                                                          0.5      15.5    94                                                           0.25     17      103                                       bis(butanoato-O)(3,3-oxetane                                                                     12       22      157                                       dimethanamine- .sub.--N, .sub.--N')platinum                                                      6        18.5    132                                                          3        15.5    111                                       Control            --       14      --                                        Cisplatin          1        16.5    118                                                          0.5      20.5    146                                                          0.25     24      171                                                          0.125    17      121                                       [3,4-dihydroxy-3-cyclobutene-                                                                    3        16      114                                       1,2-dionato(2-)-O.sup.3 ,O.sup.4 ](3,3-                                       oxetanedimethanamine- .sub.--N, .sub.--N')-                                   platinum                                                                      Control            --       14      --                                        Cisplatin          1        16.5    118                                                          0.5      20.5    146                                                          0.25     24      171                                                          0.125    17      121                                       [1,1-cyclobutanedicarboxylato-                                                                   50       20      143                                       (2-)-O.sup. 1,O.sup.1 ](3,3-oxetanedi-                                                           25       21      150                                       methanamine- .sub.--N, .sub.--N')platinum                                                        12       20.5    146                                                          6        19      136                                       Control            --       14      --                                        Cisplatin          1        16.5    118                                                          0.5      20.5    146                                                          0.25     24      171                                                          0.125    17      121                                       ______________________________________                                    

LYMPHOCYTIC LEUKEMIA L1210 TEST

The animals used BDF₁ of CD₂ F₁ mice, all of one sex, weighing a minimumof 17 g and all within a 3 g weight range. There were 6 mice in eachtest group and 18 in control groups. The tumor transplant was byintraperitoneal injection of 0.5 ml of lymphocytic leukemia L1210 at aconcentration of 10⁵ cells per mouse. The test compounds wereadministered on days, 1, 5 and 9 (relative to tumor inoculaion) atvarious doses. The mice were weighed and survivors recorded on a regularbasis for 30 days. The median survival time and the ratio of survivaltime for treated (T)/control (C) animals were calculated. The positivecontrol compound was Cisplatin given intraperitoneally at the indicateddoses. The results of this test on representative compounds of thisinvention appear in Table IV.

                  TABLE IV                                                        ______________________________________                                        Lymphocytic Leukemia L1210 Test                                                                         Median                                                               Dose     Survival T/C × 100                            Compound         (mg/kg)  (Days)   (%)                                        ______________________________________                                        dichloro(3,3-oxetanedimethan-                                                                  6.2      10       111                                        amine- .sub.--N, .sub.--N')platinum                                                            3.1      12.5     139                                        Control          --       9        --                                         Cisplatin        2.5      14       156                                                         1.25     12.5     139                                        (3,3-oxetanedimethanamine-                                                                     50       13.5     150                                         .sub.--N, .sub.--N')[propanedioato(2-)-O.sup.1,O.sup.3 ]-                                     25       10.5     117                                        platinum         12.5     9.5      106                                        Control          --       9        --                                                          5        19       211                                                         2.5      13.5     150                                                         1.25     10       111                                        bis(acetato-O)(3,3-oxetanedim-                                                                 12.5     13       144                                        ethanamine- .sub.--N, .sub.--N')platinum                                                       6.2      11       122                                                         3.1      9.5      106                                        Control          --       9        --                                         Cisplatin        5        19       211                                                         2.5      13.5     150                                                         1.25     10       111                                        bis(butanoato-O)(3,3-oxetanedi-                                                                25       14.5     161                                        methanamine- .sub.--N, .sub.--N')platinum                                                      12.5     12.5     139                                                         6.2      9.5      106                                        Control          --       9        --                                         Cisplatin        5        16       178                                                         2.5      12.5     139                                                         1.25     10       111                                        [3,4-dihydroxy-3-cyclobutene-                                                                  25       10.5     117                                        1,2-dionato(2-)-O.sup.3,O.sup.4 ](3,3-oxe-                                                     12.5     13       144                                        tanedimethanamine- .sub.--N, .sub.--N')                                                        6.2      9.5      106                                        platinum         3.1      9.5      106                                        Control          --       9        --                                         Cisplatin        5        16       178                                                         2.5      12.5     139                                                         1.25     10       111                                        [1,1-cyclobutanedicarboxylato-                                                                 50       14       156                                        (2-)-O.sup.1,O.sup.1 ](3,3-oxetanedimethan-                                                    25       13       144                                        amine- .sub.--N, .sub.--N')platinum                                                            12.5     10       111                                        Control          --       9        --                                         Cisplatin        5        16       178                                                         2.5      12.5     139                                                         1.25     10       111                                        ______________________________________                                    

M5076 SARCOMA

The M5076 reticular cell Sarcoma is propagated as subcutaneous implantsin C57B2/6 female mice. In the assays for antitumor activity, BDF₁ miceof either sex were inoculated intraperitoneally (ip) with 0.5 ml of a10% tumor brei. Test compounds were administered ip on days 1, 5, 9, 13and 17 relative to tumor inoculation on day zero. The median survivaltime in days was determined for each drug dose used on day 60 and theratio of survival time for treated (T)/control (C) animals werecalculated.

The results of this test on representative compounds of this inventionappear in Table V, compared to the results obtained with Cisplatin.

                  TABLE V                                                         ______________________________________                                        M5076 Sarcoma Test                                                                                      Median                                                               Dose     Survival T/C × 100                            Compound         (mg/kg)  (Days)   (%)                                        ______________________________________                                        (3,3-oxetanedimethanamine-                                                                     25       >60      >240                                        .sub.--N, .sub.--N')[propanedioato(2-)-O.sup.1,O.sup.3 ]-                                     12       51.5     204                                        platinum         6        55.5     222                                                         3        44.5     178                                        Control          --       25       --                                         Cisplatin        0.8      >60      >240                                       bis(acetato-O)(3,3-oxetane                                                                     6        >60      >240                                       dimethamine- .sub.--N, .sub.--N')platinum                                                      3        59.5     238                                                         1.5      50       200                                                         0.8      44.5     178                                        Control          --       25       --                                         Cisplatin        0.8      >60      >240                                       bis(butanoato-O)(3,3-oxetane-                                                                  12       45       180                                        dimethanamine- .sub.--N, .sub.--N')platinum                                                    6        37.5     150                                                         3        37.5     150                                                         1.5      35       140                                        Control          --       25       --                                         Cisplatin        0.8      >60      >240                                       [3,4-dihydroxy-3-cyclobutene-                                                                  6        43       172                                        1,2-dionato(2-)-O.sup.3,O.sup.4 ](3,3-oxe-                                                     3        36       144                                        tanedimethanamine- .sub.--N, .sub.--N')                                                        1.5      35       140                                        platinum         0.8      34.5     138                                        Control          --       25       --                                         Cisplatin        1.6      >60      >240                                                        0.8      31.5     126                                        [1,1-cyclobutanedicarboxylato-                                                                 25       >60      >240                                       (2-)-O.sup.1,O.sup.1 ](3,3-oxetanedi-                                                          12       55       220                                        methanamine- .sub.--N,  .sub.--N')platinum                                                     6        54       216                                                         3        41.5     166                                        Control          --       25       --                                         Cisplatin        1.6      >60      >240                                                        0.8      31.5     126                                        ______________________________________                                    

The invention includes novel compositions of matter and the method ofinducing the regression and/or palliation of leukemia and relatedcancers in mammals using the novel compounds of this invention whenadministered in amounts ranging from about 1 mg to about 1.2 g persquare meter of body surface area per day. The interrelationship ofdosages for animals of various sizes and species and humans (based onmg/m² of surface area) is described by Freireich, E. J., et al.,Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat,Hamster, Dog, Monkey and Man. Cancer Chemother. Rep., 50, No. 4,219-244, May 1966. A preferred dosage regimen for optimum results wouldbe from about 3 mg/m² /day to about 200 mg/m² /day, and such dosageunits are employed that a total of from about 5 mg to about 360 mg ofthe active compound for a subject of about 70 kg of body weight areadministered in a 24 hour period. This dosage regimen may be adjusted toprovide the optimum therapeutic response. For example, several divideddoses may be administered daily or the dose may be proportionallyreduced as indicated by the exigencies of the therapeutic situation. Theactive compound may be administered by the intravenous, intramuscular orsubcutaneous routes.

The active compounds may be administered parenterally. Solutions ordispersions of the active compound can be prepared in water, suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersions canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof in oils. Under ordinary conditions of storage and use thesepreparations contains a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, liquidpolyethylene glycol), suitable mixtures thereof and vegetable oils. Theproper fluidity can be maintained, for example, by the use of a coatingsuch as lecithin, by the maintenance of the required particle size inthe case of dispersion and by the use of surfactants. The prevention ofthe action of microorganisms can be brought about by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal and the like. In manycases it will be preferable to include isotonic agents for example,sugars or sodium chloride. Prolonged absorption of the injectablecompositions can be obtained by the use in the compositions of agentswhich delay absorption, for example, aluminum monostearate and gelatin.Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

As used herein "pharmaceutically acceptable carrier" includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subject to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the novel dosageunit forms of the invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such an active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is imparied as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitable,pharmaceutically acceptable carrier in dosage unit form as hereinbeforedisclosed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 2 mg to about 2 g, withfrom about 5 to about 360 mg being preferred. Expressed in proportions,the active compound is generally present in from about 2 to about 100mg/ml of carrier. In the case of compositions containing supplementaryactive ingredients, the dosages are determined by reference to the usualdose and manner of administration of the said ingredients.

Regression and palliation of cancers are attained, for example, usingintraperitoneal administration. A single, intravenous dosage or repeateddaily dosages can be administered. Daily dosages up to about 5 or 10days are often sufficient. It is also possible to dispense one dailydosage or one dose on alternate or less frequent days. As can be seenfrom the dosage regimens, the amount of principal active ingredientadministered is sufficient amount to aid regression and palliation ofthe leukemia or the like, in the absence of excessive deleterious sideeffects of a cytotoxic nature to the host harboring the cancer. As usedherein, cancer disease means blood malignancies such as leukemia, aswell as other solid and non-solid malignancies such as themelanocarcinomas, lung carcinomas and mammary tumors. By regression andpalliation is meant arresting or retarding the growth of the tumor orother manifestation of the disease compared to the course of the diseasein the absence of treatment.

This invention will be described in greater detail in conjunction withthe following, non-limiting specific examples.

EXAMPLE 1 Dichloro(3,3-oxetanedimethanamine-N,N')platinum

A mixture 162 g of tribromo pentaerythritol, 28.6 g of potassiumhydroxide and 910 ml of methanol was heated at reflux for 6 hours, thenfiltered. The filtrate was evaporated to dryness and the residuetriturated with ether, then filtered. The filtrate was vacuum distilled,giving 62.88 g of 3,3-bis(bromomethyl)oxetane (70°-73° C., 1.0-1.5 mm).

A 9.76 g portion of 3,3-bis(bromomethyl)oxetane in 30 ml of methanol wascooled in an ice bath and 13 g of dry ammonia absorbed. The reaction wassealed and the mixture stirred at room temperature for 40 hours, thenevaporated to dryness. A 2.60 g portion of this residue was slurried in10 ml of methanol and treated with a solution of 1.08 g of sodiummethoxide in 15 ml of methanol. This mixture was cooled in an ice bath,stirred for 15 minutes, then evaporated to dryness. The residue wastriturated with isopropanol and filtered. The filtrate was treated with20 ml of 6N hydrochloric acid in isopropanol, stirred for 1/2 hour andthe solid collected washed with isopropanol and dried, giving 1.32 g of3,3-oxetanedimethanamine, dihydrochloride, mp 236° C. (dec.).

A 945 mg portion of 3,3-oxetanedimethanamine dihydrochloride in 40 ml ofwater was treated with 820 mg of sodium acetate and 2.075 g of potassiumtetrachloroplatinate. This mixture was stirred for 3 hours, thenfiltered. The filtrate was allowed to stand overnight, then theresulting solid was collected, giving 440 mg of the desired product asyellow crystals, mp 270°-273° C.

EXAMPLE 2 [1,1,2-Ethanetricarboxylato(2-)-0¹,0¹](3,3-oxetanedimethanamine-N,N')platinum

A 764 mg portion of dichloro(3,3-oxetanedimethanamine-N,N')platinum in 5ml of water was treated with a solution of 612 mg of silver nitrate in 5ml of water. This solution was stirred for 1/2 hour, then filtered andthe filtrate treated with a solution of 324 mg of diglycolic acid, 4 mlof 1N sodium hydroxide and 5 ml of water. This mixture was stirred for 2days and then filtered. The filtrate was refrigerated for 7 days. Theresulting solid was collected, washed with methanol and dried, giving 50mg of the desired product, mp 275°-280° C.

EXAMPLE 3 Bis(butanoato-0)(3,3-oxetanedimethanamine-N,N')platinum

A 764 mg portion of dichloro(3,3-oxetanedimethanamine-N,N')platinum in 5ml of water was treated with a solution of 680 mg of silver nitrate in 5ml of water. This solution was stirred for 1/2 hour, then filtered andthe filtrated treated with 352 mg of butanoic acid in 4 ml of 1N sodiumhydroxide and 5 ml of water. This mixture was stirred, then allowed tostand overnight and then filtered. The filtrate was concentrated todryness, then triturated in water and dried, giving 300 mg of thedesired product, mp 205°-210° C. (dec.).

EXAMPLE 4 [3,4-Dihydroxy-3-cyclobutene-1,2-dionato(2-)-0³,0⁴](3,3-oxetanedimethanamine-N,N')platinum

A 764 mg portion of dichloro(3,3-oxetanedimethanamine-N,N')platinum wasreacted with 680 mg of silver nitrate as described in Example 2. Thefiltrate was treated with a solution of 228 mg of3,4-dihydroxy-3cyclobutene-1,2-dicarboxylic acid in 4 ml of 1N sodiumhydroxide and 5 ml of water. The reaction was allowed to stand for 2hours, then the solid was collected, washed with water and dried, giving100 mg of the desired product as a yellow solid, mp 275°-280° C. (dec.).

EXAMPLE 5 [1,1-Cyclobutanedicarboxylato(2-)-0¹,0¹](3,3-oxetanedimethanamine-N,N')platinum

A suspension of 760 mg ofdichloro(3,3-oxetanedimethanamine-N,N')platinum and 716 mg of thedisilver salt of 1,1-cyclobutanedicarboxylic acid in 50 ml of water wasstirred in the dark for 64 hours, then filtered. The filtrate wasconcentrated to dryness, giving 780 mg of the desired product, mp280°-290° C. (dec.).

EXAMPLE 6(3,3-Oxetanedimethanamine-N,N')[[2,2'-oxybis[acetato]](2-)-0¹,0¹]platinum

A mixture of 764 mg of dichloro(3,3-oxetanedimethanamine-N,N')platinumand 696 mg of the disilver salt of diglycolic acid in 50 ml of water wasstirred in the dark overnight and then filtered. The filtrate wasevaporated to dryness, giving 880 mg of the desired product as acolorless glass, mp 225°-228° C.

EXAMPLE 7 (3,3-Oxetanedimethanamine-N,N')[propanedioato(2-)-0¹,0³]platinum, heptahydrate

A mixture of 764 mg of dichloro(3,3-oxetanedimethanamine-N,N')platinumand 680 mg of silver nitrate in water was stirred for 1/2 hour and thenfiltered. The filtrate was treated with 208 mg of malonic acid and 4 mlof 1N sodium hydroxide. This mixture was allowed to stand for 3 days andthe resulting crystals collected, giving 700 mg of the desired product,mp 275°-285° C. (dec.).

EXAMPLE 8 (3,3-Oxetanedimethanamine-N,N')[propanedioato (2-)-0¹,0³]platinum, dihydrate

The procedure of Example 7 was repeated. The crystalline product wasrecrystallized from 10 ml of water, giving 360 mg of the desiredproduct, mp 275°-280° C. (dec.).

EXAMPLE 9 (3,3-Oxetanedimethanamine-N,N')[pentanedioato(2-)-0¹,0⁵]platinum

A mixture of 382 mg of dichloro(3,3-oxetanedimethanamine-N,N')platinumand 345 mg of glutaric acid in 30 ml of water was stirred in the darkovernight and then filtered. The filtrate was evaporated to dryness,giving 410 mg of the desired product as a colorless solid, mp 220°-222°C. (dec.).

EXAMPLE 10 Bis(acetato-0) (3,3-oxetanedimethanamine-N,N')platinum

A mixture of 764 mg of dichloro(3,3-oxetanedimethanamineN,N')platinumand 668 mg of silver acetate in 50 ml of water was stirred for 2 daysand then filtered. The filtrate was concentrated to dryness, giving 800mg of the desired product as a pale yellow solid, mp >200° C.

EXAMPLE 11(3,3-Oxetanedimethanamine-N,N')[[2,2-sulfonylbis[acetato]](2-)-0¹,0.sup.1]platinum

A 1.14 g portion of dichloro(3,3-oxetanedimethanamine-N,N')platinum wassuspended in 75 ml of water and treated with 1.18 g of sulfonyldiaceticacid disilver salt. The mixture was stirred for 4 hours at roomtemperature and then filtered. The filtrate was concentrated to about 50ml, allowed to stand 48 hours and the resulting said collected, giving470 mg of the desired product as a pale purple solid with no definedmelting point below 300° C.

EXAMPLE 12 Dichloro(tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum

A mixture of 28.6 g of dichloroethyl ether, 13.2 g of malononitrile,55.28 g of potassium carbonate and 800 ml of acetonitrile was refluxedon a steam bath for 24 hours, then filtered while hot. The filtrate wasevaporated and the residue crystallized with charcoal treatment from 100ml of ethanol, giving 9.5 g of tetrahydro-4H-pyran-4,4-dicarbonitrile ascolorless plates, mp 110°-112° C.

A 180 ml portion of 1N borane in tetrahydrofuran was added rapidly, butdropwise, to a solution of 8.18 g oftetrahydro-4H-pyran-4,4-dicarbonitrile in 150 ml of tetrahydrofuran.This mixture was warmed, then cooled to room temperature in an ice bathand then stirred for 64 hours at room temperature. A 100 ml portion ofethanol was added dropwise, then the mixture was stirred for 4 hours andevaporated to dryness. The residue was taken up in 100 ml of water,acidified with 50 ml of 6N hydrochloric acid and extracted three timeswith ether. The remaining aqueous layer was evaporated to dryness. Theresidue was boiled in 300 ml of methanol and filtered while hot. Thefiltrate was treated with 200 ml of ether and cooled. The resultingsolid was collected, washed with ether and dried, giving 8.31 g oftetrahydro-4H-pyran-4,4-dimethanamine, dihydrochloride, mp 258°-262° C.(dec.).

A mixture of 2.17 g of the above compound and 1.64 g of sodium acetatein 50 ml of water was treated with 4.15 g of potassiumtetrachloroplatinate. The reaction was repeatedly filtered to removesuccesive crops of black to red crystals. When no more precipitatesformed the mixture was allowed to stand overnight. The gold crystalswere collected, giving 400 mg of the desired product, mp 280°-282° C.(dec.).

EXAMPLE 13 [1,1-Cyclobutanedicarboxylato(2-)-0¹,0¹]tetrahydro-4H-pyran-4,4-dimethanamine-N,N') platinum

A mixture of 0.82 g ofdichloro(tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum and 0.716 gof the disilver salt of 1,1-cyclobutanedicarboxylic acid in 75 ml ofwater was stirred in the dark overnight and then filtered and washedwith water. The combined filtrate and wash was evaporated to dryness,giving 0.72 g of the desired product, mp 290°-295° C. (dec.).

EXAMPLE 14 [[2,2'-oxybis[acetato]](2-)-0¹,0¹](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum

The procedure of Example 13 was repeated, using 0.7 g of the disilversalt of 2,2'-oxybisacetic acid in place of the disilver salt of1,1-cyclobutanedicarboxylic acid, giving 1.0 g of the desired product,mp 218°-220° C. (dec.).

EXAMPLE 15 [Propanedioato(2-)-0¹,0³](tetrahydro-4H-pyran-(4,4-dimethanamine-N,N')platinum

The procedure of Example 13 was repeated, using 0.64 g of the disilversalt of malonic acid in place of the disilver salt of1,1-cyclobutanedicarboxylic acid, giving 0.57 g of the desired product,mp 250°-255° C.

EXAMPLE 16 [3,4-Dihydroxy-3-cyclobutene-1,2-dionato(2-)-0³,0⁴](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum

The procedure of Example 13 was repeated, using 0.66 g of the disilversalt of 3,4-dihydroxy-3-cyclobutene-1,2-dicarboxylic acid in place ofthe 1,1-cyclobutanedicarboxylic acid, giving 0.3 g of the desiredproduct, mp 180°-185° C. (dec.).

EXAMPLE 17(Tetrahydro-4H-pyran-4,4-dimethanamine-N,N')tetrachloroplatinum

A 1.8 g portion ofdichloro(tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum issuspended in 40 ml of 0.5N hydrochloric acid and heated to 100° C. Aslow stream of chlorine gas is bubbled through the reaction mixture.Within a few minutes a clear solution is obtained. Bubbling of chlorinegas is continued for 2 hours. Nitrogen is bubbled through the reactionmixture to remove chlorine gas and the solution evaporated to dryness invacuo. The yellow residue is taken up in 250 ml of methanol and thesolution is filtered. The filtrate is evaporated to give 1.0 g of thedesired product as a yellow solid.

EXAMPLE 18[1,1-Cyclobutanedicarboxylato(2-)-0,0'](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')dihydroxyplatinum

A 1.2 g portion of [1,1-cyclobutanedicarboxylato(2-)-0¹,0¹](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum is suspended in 5ml of distilled water. A 25 ml portion of 30% hydrogen peroxide isadded. Stirring is carried out during 0.5 hour at room temperature,thereafter one hour under reflux. The suspension is cooled and the solidsubstance is filtered, washed with water and dried under reducedpressure, giving 0.4 g of the desired product.

EXAMPLE 19 [L-Threo-3-hexulosonato(2-)C²,O⁵-gamma-lactone](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum

A solution of 1.36 g of silver nitrate in 10 ml of water was added to asuspension of 1.64 g ofdichloro(tetra-hydro-4H-pyran-4,4-dimethanamine-N,N')platinum in 100 mlof water and stirred in the dark for 4 hours followed by filtration. Thefiltrate was mixed with a solution of 1.58 g of L-ascorbic acid sodiumsalt in 10 ml of water and then filtered. The filtrate was stirred inthe dark overnight and then refiltered. This filtrate was evaporated todryness, the residue dissolved in 5 ml of water and added to 200 ml ofethanol. The resulting suspension was refrigerated for 2 hours and thesolid collected, giving 1.07 g of the desired product.

EXAMPLE 20 Tetrahydro-4H-thiopyran-4,4-dimethanamine, 1,1-dioxide

A mixture of 38.2 g of bis(2-chloroethyl)sulfone, 13.2 g ofmalononitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrileis refluxed on a steam bath for 24 hours, then filtered while hot. Thefiltrate is evaporated and the residue crystallized with charcoaltreatment from 100 ml of ethanol, giving 10.6 g oftetrahydro-4H-thiopyran-4,4-dicarbonitrile, 1,1-dioxide as colorlesscrystals.

A 180 ml portion of 1N borane in tetrahydrofuran is added rapidly, butdropwise, to a solution of 11.05 g oftetrahydro-4H-thiopyran-4,4-dicarbonitrile, 1,1-dioxide in 150 ml oftetrahydrofuran. This mixture is warmed, then cooled to room temperaturein an ice bath and then stirred for 64 hours at room temperature. A 100ml portion of ethanol is added dropwise, then the mixture is stirred for4 hours and then evaporated to dryness. The residue is taken up in 100ml of water, acidified with 50 ml of 6N hydrochloric acid and extractedthree times with ether. The remaining aqueous layer is evaporated todryness. The residue is boiled in 300 ml of methanol and filtered whilehot. The filtrate is treated with 200 ml of ether and cooled. Theresulting solid is collected, washed with ether and dried, giving 9.1 gof the desired product.

EXAMPLE 21Dichloro(tetrahydro-4H-thiopyran-4,4-dimethanamine-1,1-dioxide-N,N')platinu

A mixture of 2.65 g of tetrahydro-4H-thiopyran-4,4-dimethanamine,1,1-dioxide and 1.64 g of sodium acetate in 50 ml of water is treatedwith 4.15 g of potassium tetrachloroplatinate. The reaction isrepeatedly filtered to remove successive crops of black to red crystals.When no more precipitates formed, the mixture is allowed to standovernight. The gold crystals are collected, giving 430 mg of the desiredproduct.

EXAMPLE 22 [1,1-Cyclobutanedicarboxylato(2-)0¹,0¹ ](tetrahydro-4H-thiopyran-4,4-dimethanamine-1,1-dioxide-N,N')platinum

A mixture of 916 mg ofdichloro(tetrahydro-4H-thiopyran-4,4-dimenthanamine-N,N')platinum and716 mg of the disilver salt of 1,1-cyclobutanedicarboxylic acid in 75 mlof water is stirred in the dark overnight, then filtered and washed withwater. The combined filtrate and wash is evaporated to dryness, giving820 mg of the desired product.

EXAMPLE 23 1-Methyl-4,4-piperidinedimethanamine, trihydrochloride

A mixture of 31.2 g of bis(chloroethyl)methylamine, 13.2 g ofmalonitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrileis refluxed on a steam bath for 24 hours, then filtered while hot. Thefiltrate is evaporated and the residue crystallized with charcoaltreatment from 100 ml of ethanol, giving 10.6 g of1-methylpiperidine-4,4-dicarbonitrile, as colorless crystals.

A 180 ml portion of 1N borane in tetrahydrofuran is added rapidly, butdropwise, to a solution of 8.95 g of1-methylpiperidine-4,4-dicarbonitrile, in 150 ml of tetrahydrofuran.This mixture is warmed, then cooled to room temperature in an ice bathand then stirred for 64 hours at room temperature. A 100 ml portion ofethanol is added dropwise, then the mixture is stirred for 4 hours andthen evaporated to dryness. The residue is taken up in 100 ml of water,acidified with 50 ml of 6N hydrochloric acid and extracted three timeswith ether. The remaining aqueous layer is evaporated to dryness. Theresidue is boiled in 300 ml of methanol and filtered while hot. Thefiltrate is treated with 200 ml of ether and cooled. The resulting solidis collected, washed with ether and dried, giving 8.51 g of the desiredproduct.

EXAMPLE 24 Dichloro(1-methylpiperidinedimethanamine-N,N')platinum

A mixture of 2.67 g of 1-methyl-4,4-piperidinedimethanamine,trihydrochloride and 2.46 g of sodium acetate in 50 ml of water istreated with 4.15 g of potassium tetrachloroplatinate. The reaction isrepeatedly filtered to remove successive crops of black to red crystals.When no more precipitates formed, the mixture is allowed to standovernight. The gold crystals are collected, giving 410 mg of the desiredproduct.

EXAMPLE 25 [1,1-Cyclobutanedicarboxylato(2-)-0¹,0¹](1-methylpiperidinedimethanamine-N,N')platinum

A mixture of 850 mg of dichloro(1-methylpiperidinedimethanamine-N,N')platinum and 716 mg of the disilver salt of 1,1-cyclobutanedicarboxylicacid in 75 ml of water is stirred in the dark overnight, then filteredand washed with water. The combined filtrate and wash is evaporated todryness, giving 780 mg of the desired product.

EXAMPLE 26 1-Acetyl-4,4-piperidinedimethanamine, dihydrochloride

A mixture of 36.8 g of N,N-bis(chloroethyl) acetamide, 13.2 g ofmalononitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrileis refluxed on a steam bath for 24 hours, then filtered while hot. Thefiltrate is evaporated and the residue crystallized with charcaoltreatment from 100 ml of ethanol, giving 10.7 g of1-acetyl-4,4-piperidine-4,4-dicarbonitrile, as colorless crystals.

A 180 ml portion of 1N borane in tetrahydrofuran is added rapidly, butdropwise, to a soluton of 10.6 g of1-acetyl-4,4-piperidine-4,4-dicarbonitrile, in 150 ml oftetrahydrofuran. This mixture is warmed, then cooled to room temperaturein an ice bath and then stirred for 64 hours at room temperature. A 100ml portion of ethanol is added dropwise, then the mixture is stirred for4 hours and then evaporated to dryness. The residue is taken up in 100ml of water, acidified with 50 ml of 6N hydrochloric acid and extractedthree times with ether. The remaining aqueous layer is evaporated todryness. The residue is boiled in 300 ml of methanol and filtered whilehot. The filtrate is treated with 200 ml of ether and cooled. Theresulting solid is collected, washed with ether and dried, giving 9.1 gof the desired product.

EXAMPLE 27 Dichloro(1-acetyl-4,4-piperidinedimethanamine-N,N')platinum

A mixture of 2.58 g of 1-acetyl-4,4-piperidinedimethanamine,dihydrochloride and 1.64 g of sodium acetate in 50 ml of water istreated with 4.15 g of potassium tetrachloroplatinate. The reaction isrepeatedly filtered to remove successive crops of black to red crystals.When no more precipitates formed, the mixture is allowed to standovernight. The gold crystals are collected, giving 420 mg of the desiredproduct.

EXAMPLE 28 [1,1-Cyclobutanedicarboxylato(2-)-0¹,0¹](1-acetyl-4,4-piperidinedimethanamine-N,N')platinum

A mixture of 906 mg ofdichloro(1-acetyl-4,4-piperidinedimethanamine-N,N')platinum and 716 mgof the disilver salt of 1,1-cyclobutanedicarboxylic acid in 75 ml ofwater is stirred in the dark overnight, then filtered and washed withwater. The combined filtrate and wash is evaporated to dryness, giving750 mg of the desired product.

What is claimed is:
 1. A compound selected from those of the formulae:##STR9## where A is O, n and n' are the same and are 2,; L and L' areselected from the group consisting of halide, nitrate, sulfate, and amonobasic carboxylate selected from the group consisting of acetate,hydroxy acetate and propionate; or L and L' may be a diabsic carboxylateselected from the group consisting of ##STR10## or L and L' takentogether may be a tribasic carboxylate seleced from the group consistingof ##STR11## or L or L' taken together is ascorbic acid and X isselected from the group consisting of halogen and hydroxy.
 2. Thecompound according to claim 1,[3,4-dihydroxy-3-cyclobutene-1,2-dionato(2-)-0³,0⁴](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum.
 3. The compounddichloro-(tetrahydro-4H-pyran-4,4-dimethanamine-N,N)platinum.
 4. Thecompound [1,1-cyclobutanedicarboxylato(2-)-0¹,0¹](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum.
 5. The compound[[2,2'-oxybis[acetato]](2-)-0¹, 0¹]tetrahydro-4H-pyran-4,4-dimethanamineN,N') tetrachloro platinum.
 6. Thecompound [propane dionato (2-)-0¹,0³](tetrahydro-4H-pyran-4,4-dimethanamine-N,N')platinum.
 7. The compoundtetrahydro-4H-pyran-4,4-dimethanamine-N,N') tetrachloroplatinum.
 8. Thecompound [1,1-cyclobutanedicarboxylato (2-)-0¹, 0¹](tetrahydro-4H-pyran-4,4-dimethanamine-N,N') dihydroxyplatinum.
 9. Thecompound [3,4-dihydroxy-3-cyclobutene-1,2-dionato(2-)-0³,0⁴](tetrahydro-4H-pyran-4,4-dimethanamine-N,N') platinum.
 10. Acomposition of matter in dosage unit form for administering byintravenous, intramuscular, subcutaneous, parenteral or intraperitonealroutes comprising an amount of from about 1 mg to about 1.2 g per squaremeter of mammalian body surface area of a compound of claim 1 inassociation with a pharmaceutically acceptable carrier.
 11. Acomposition of matter, in dosage unit form for administering byintravenous, intramuscular, subcutaneous, parenteral or intraperitonealroutes, which consists essentially of an amount of fromm about 1 mg toabout 1.2 g per square meter of mammalian body surface area of acompound of claim 1 in association with a pharmaceutically acceptablecarrier.
 12. A composition of matter, in dosage unit form foradministering by intravenous, intramuscular, subcutaneous, parenteral orintraperitoneal routes, which consists of an amount of from about 1 mgto about 1.2 g per square meter of mammalian body surface area of acompound of claim 1 in association with a pharmaceutically acceptablecarrier.
 13. A composition of matter on dosage unit form foradministering by intravenous, intramuscular, subcutaneous, parenteral orintraperitoneal routes which comprises an amount of from about 1 mg toabout 1.2 g per square meter of mammalian body surface area of acompound of claim 4 association with a pharmaceutically acceptablecarrier.
 14. A composition of matter in dosage unit form foradministering by intravenous, intramuscular, subcutaneous, parenteral orintraperitoneal routes which comprises an amount of from about 1 mg toabout 1.2 g per square meter of mammalian body surface area of acompound of claim 5 association with a pharmaceutically acceptablecarrier.
 15. A composition of matter in dosage unit form foradministering by intravenous, intramuscular, subcutaneous, parenteral orintraperitoneal routes which comprises an amount of from about 1 mg toabout 1.2 g per square meter of mammalian body surface area of acompound of claim 6 association with a pharmaceutically acceptablecarrier.
 16. A composition of matter in dosage unit form foradministering by intravenous, intramuscular, subcutaneous, or parenteralor intraperitoneal routes which comprises an amount of from about 1 mgto about 1.2 g per square meter of mammalian body surface area of acompound of claim 7 association with a pharmaceutically acceptablecarrier.
 17. A composition of matter in dosage unit form foradministering by intravenous, intramuscular, subcutaneous, parenteral orintraperitoneal routes which comprises an amount of from about 1 mg toabout 1.2 g per square meter of mammalian body surface area of acompound of claim 8 association with a pharmaceutically acceptablecarrier.
 18. A method of treating melanocarcinomas, lung carcinomas andmammary tumors in warm-blooded animals which comprises administering aneffective, oncolytic amount of a compound of claim
 1. 19. A method oftreating melanocarcinomas, lung carcinoma and mammary tumors inwarm-blooded animals which comprises administering an affectiveoncolytic amount of a compound of claims 4, 5, 6, 7 or 8.